The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis - providing D2HG interstitial fluid concentrations - sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 μM awake and 117.6 ± 98.6 μM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis.

Objectives: Persistent high-risk human papillomavirus infection is a major factor in the development of cervical intraepithelial neoplasia and cervical cancer. However, the exact point during this infection that cervical intraepithelial neoplasia develops has eluded researchers. Therefore, we designed a study investigating infection duration between the recorded onset of persistent high-risk human papillomavirus infection and cervical intraepithelial neoplasia development. Methods: Basic descriptive statistics, including the Chi-square test and the Kaplan-Meier method, were used to retrospectively analyze data of 277 women who underwent human papillomavirus genotyping, exhibited persistent high-risk human papillomavirus infection, were cervical cytology negative at enrollment, and developed cervical intraepithelial neoplasia at some point during follow-up. Results: Mean number of cervical cytology and human papillomavirus tests was 2.31 per patient (range: 2-8). Human papillomavirus 16, 52, 58, and 33 accounted for 21.64% (132/610), 21.64% (132/610), 15.90% (97/610), and 10.66% (65/610) of infections, respectively. 42.24% (117/277) and 57.76% (160/277) of women were diagnosed with cervical intraepithelial neoplasia 1 and cervical intraepithelial neoplasia 2+ after persistent high-risk human papillomavirus infection, with mean follow-up times of 18.15 (11.81) and 19.82 (13.31) months, respectively. Cervical intraepithelial neoplasia occurred between 4 and 70 months following the recorded onset of persistent high-risk human papillomavirus infection and 73.65% (204/277) of women developed cervical intraepithelial neoplasia within 24 months. Conclusion: Human papillomavirus 16, 52, 58, and 33 were the most prevalent high-risk human papillomavirus types in a group of women in which the majority developed cervical intraepithelial neoplasia within 24 months of persistent infection.

Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the miR-124 acts as a safeguard to inhibit the pro-inflammatory production and reparative regeneration.

A translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 which is a rare cytogenetic abnormality in CLL patients, has a more aggressive clinical course with a shorter time to first treatment (TTT) and worse overall survival (OS). To date, there is no literature reporting the identification of the t(14;19) in Chinese CLL patients and the reviewing the characteristic of all patients with this abnormality reported previously in the literature.

Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.

This study aimed at investigating the anticancer potential of the recombinant adenovirus Ad-apoptin-hTERTp-E1a (Ad-VT) and its synergistic combination with paclitaxel (PTX) in breast cancer treatment. First, we used the Calcusyn software to analyze the synergy between the Ad-VT and paclitaxel, and to determine the final drug concentration. Second, we used crystal violet staining and WST-1 assays to analyze the inhibitory effect of Ad-VT and paclitaxel combination treatment on MCF-7, MDA-MB-231, and MCF-10A cells. Subsequently, we used Hoechst, Annexin V, JC-1 staining to analyze the inhibition pathway of drugs on breast cancer cells. We also used Transwell assays to analyze the cell migration and invasion of MCF-7 and MDA-MB-231 cells. The pGL4.51 plasmid was used to transfect and to generate MDA-MB-231 cells, that stably express luciferase (MDA-MB-231-LUC). The in vivo tumor inhibition effect of Ad-VT and paclitaxel combination treatment was subsequently confirmed using a tumor-bearing nude mouse model. This combination treatment can increase the inhibition of breast cancer cells and reduce paclitaxel toxicity. Ad-VT had a strong apoptosis-inducing effect on MCF-7 and MDA-MB-231 cells, that was mainly mediated through the mitochondrial apoptotic pathway. The combination of Ad-VT and paclitaxel could significantly increase the inhibition of breast cancer cell migration and invasion. Combination of Ad-VT and paclitaxel can inhibit tumor growth and reduce toxicity in vivo. Ad-VT can also inhibit the growth of breast cancer cells and promote their apoptosis. Meanwhile, when it is combined with paclitaxel, Ad-VT could play a significant role in a synergistic tumor inhibition.

Background: Platinum-based agents, including cisplatin, carboplatin, and oxaliplatin, are indispensable for the treatment of lung cancer. The development of toxicity frequently necessitates dose reduction or discontinuation of therapy, despite the clinical response. Pharmacogenomics studies were reviewed to identify the possible genetic variants that underlie individual susceptibility to platinum-related toxicities. Method: We conducted a systematic search in PubMed and Embase for pharmacogenomics reports that focused on commonly reported platinum-induced toxicities, such as gastrointestinal (GI), hematological, neurological, and other toxicities, in patients diagnosed with lung cancer. Meta-analyses were conducted to determine the association between genetic polymorphisms and platinum-induced toxicity by checking the odds ratio (OR) and 95% confidence interval (CI) using random or fixed-effects models as appropriate. Results: Twenty eligible studies that met the inclusion criteria with sufficient data were extracted and presented comprehensively. A total of 16 polymorphisms from 11 genes were included in the meta-analysis. MTHFR rs1801131 and MDM2 rs1690924 were significantly correlated with platinum-induced GI toxicity (P = 0.04 and P = 0.02, respectively). Patients with the MTHFR rs1801131AA and MDM2 rs1690924TC/CC genotype tended to have a higher risk of GI toxicity than patients with other genotypes did (OR = 1.73, 95% CI = 0.86-2.18; and OR = 0.51, 95% CI = 0.29-0.88, respectively). Compared to carriers of the MTHFR rs1801133CC genotype, carriers of the CT/TT genotype had a significantly increased risk of hematological toxicity (P = 0.01, OR = 1.68, 95% CI = 1.12-2.52). Conclusion: In the future, physicians should pay careful attention to MTHFR and MDM2 for personalized chemotherapy treatment among patients with lung cancer.

Background: Several recent studies have reported the reliable prognostic effect of hematological biomarkers in various tumors. Yet, the prognostic value of these hematological markers in soft tissue sarcoma (STS) remains inconclusive. Thus, the aim of this meta-analysis was to check the effect of hematological markers on the prognosis of STS. Methods: We systematically searched for relevant papers published before October 2019 in the PubMed and EMBASE databases. Overall survival (OS) and disease-specific survival (DSS) were the primary outcome, whereas disease-free survival was the secondary outcome. A thorough study of hazard ratios (HR) and 95% of confidence intervals (CIs) was done for determining the prognostic significance. Results: We performed 23 studies that comprised of 4,480 patients with STS. The results revealed that higher neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and platelet-to-lymphocyte ratio (PLR) were associated with poor OS/DFS (HR = 2.08/1.72, for NLR; HR = 1.92/1.75, for CRP, and HR = 1.86/1.61, for PLR). In contrast, a low lymphocyte-to-monocyte ratio (LMR) was relate to worse OS/DFS (HR = 2.01/1.90, for LMR). Moreover, pooled analysis illustrated that elevated NLR and CRP represents poor DSS, with HRs of 1.46 and 2.06, respectively. In addition, combined analysis revealed that higher Glasgow prognostic score (GPS) was linked to an adverse OS/DSS (HR = 2.35/2.77). Conclusion: Our meta-analysis suggested that hematological markers (NLR, CRP, PLR, LMR, and GPS) are one of the important prognostic indicators for patients affected by high-grade STS and patients with the STS being located in the extremity.

Background and Aim: Bromodomain and extraterminal domain (BET) family proteins are epigenetic regulators involved in human malignances. Targeting BET proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer therapeutics. BET proteins have been found to be overexpressed in HCC cells and tumor tissues. However, the biological activity of BET-PROTACs in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated anti-HCC activity of BETd-260, a BET-PROTAC molecule using in vitro and in vivo models. Methods: BETd-260-mediated anti-HCC activity was investigated by cell viability, apoptosis assays. Efficacy was examined with a cell lines-derived HCC xenograft model in mice. Anticancer mechanism was investigated by RT-PCR, western blotting and immunohistochemical staining. Results: BETd-260 potently suppressed cell viability and robustly induced apoptosis in HCC cells. BETd-260 reciprocally modulated the expression of several apoptotic genes in HCC cells, i.e., suppressing the expression of anti-apoptotic Mcl-1, Bcl-2, c-Myc, and X-linked inhibitor of apoptosis (XIAP), whereas increasing the expression of pro-apoptotic Bad. BETd-260 treatment led to disruption of mitochondrial membrane integrity, and triggered apoptosis via intrinsic signaling in HCC cells. BETd-260 triggered apoptosis in HCC xenograft tissue and profoundly inhibited the growth of HCC xenograft tumors in mice. Conclusion: Our data suggest that pharmacological targeting of BET for degradation may be a novel therapeutic strategy for the treatment of HCC.

Introduction: Disparities in the incidence, mortality, and survival of cancer types between urban and rural areas in China reflect the effects of different risk factor exposure, education, and different medical availability. We aimed to characterize the disparities in the incidence, mortality, and survivals of cancer types between urban and rural areas in Shanghai, China, 2002-2015. Materials and Methods: The incidence and mortality were standardized by Segi's world standard population. Trends in the incidence and mortality of cancers were compared using annual percent change. The 5-year observed and relative survivals were calculated with life table and Ederer II methods. Results: Age-standardized incidences and mortalities were 212.55/105 and 109.45/105 in urban areas and 210.14/105 and 103.99/105 in rural areas, respectively. Female breast cancer and colorectal cancer occurred more frequently in urban than in rural areas, quite in contrast to liver cancer and cervical cancer. Cancers of lung and bronchus, liver, stomach, and colon and rectum were the leading causes of cancer death in both areas. Age-standardized incidence of female breast cancer and colorectal cancer in urban areas increased while gastric cancer and liver cancer decreased in both areas. Age-standardized mortalities of cancers of breast, esophagus, stomach, colon and rectum, liver, and lung and bronchus decreased in both areas. For all cancers combined, the 5-year observed and relative survivals of cancer patients were higher in urban than in rural areas. The 5-year observed and relative survivals of cancers of liver, pancreas, stomach, brain and central nervous system (CNS), and prostate were higher in urban than in rural areas. The 5-year observed and relative survivals of cervical cancer were higher in rural than in urban areas. Conclusions: Factors promoting female breast cancer and colorectal cancer in urban areas and liver cancer and cervical cancer in rural areas should be specifically intervened in cancer prophylaxis. Improved medical services can greatly prolong the survival of major cancers in rural areas.

Objectives: This study aimed to explore the predictive value of MRI-based radiomic model for progression-free survival (PFS) in nonmetastatic nasopharyngeal carcinoma (NPC). Methods: A total of 327 nonmetastatic NPC patients [training cohort (n = 230) and validation cohort (n = 97)] were enrolled. The clinical and MRI data were collected. The least absolute shrinkage selection operator (LASSO) and recursive feature elimination (RFE) were used to select radiomic features. Five models [Model 1: clinical data, Model 2: overall stage, Model 3: radiomics, Model 4: radiomics + overall stage, Model 5: radiomics + overall stage + Epstein-Barr virus (EBV) DNA] were constructed. The prognostic performances of these models were evaluated by Harrell's concordance index (C-index). The Kaplan-Meier method was applied for the survival analysis. Results: Model 5 incorporating radiomics, overall stage, and EBV DNA yielded the highest C-indices for predicting PFS in comparison with Model 1, Model 2, Model 3, and Model 4 (training cohorts: 0.805 vs. 0.766 vs. 0.749 vs. 0.641 vs. 0.563, validation cohorts: 0.874 vs. 0.839 vs. 836 vs. 0.689 vs. 0.456). The survival curve showed that the high-risk group yielded a lower PFS than the low-risk group. Conclusions: The model incorporating radiomics, overall stage, and EBV DNA showed better performance for predicting PFS in nonmetastatic NPC patients.

The survival rate of breast cancer (BC) patients remains poor, thus the identification of safe and effective new drugs is crucial to improve therapeutic outcomes and overall survival. Pinocembrin (PCB), a pharmacologically active ingredient of Pinus heartwood, Eucalyptus, Euphorbia, Populus, and Sparattosperma leucanthum, has been widely applied for the treatment of various diseases and possesses anticancer activities. In vitro assays were performed to investigate the antiproliferation and antimetastasis activities of PCB in BC cells. A tumorigenesis assay with the use of murine BC models was performed to assess the antiproliferation activities of PCB in vivo. Moreover, the molecular mechanisms underlying the anticancer activities of PCB in BC cells were explored. The results showed that the anti-inhibitory and antiproliferation activities of PCB in BC might involve cell cycle (G2/M phase) arrest and apoptosis. PCB downregulated the expression levels of proteins involved in cell cycle progression and apoptosis, including cyclinB1, Cdc2, PARP1, Bcl-2, and survivin, and upregulated protein levels of cleaved PARP1, cleaved caspase3, cleaved caspase9, and BAX. In a murine subcutaneous tumor model, PCB suppressed the growth of MCF-7 cells in vivo. Low concentrations of PCB also significantly inhibited the migration and invasion abilities of BC cells. Mechanistically, PCB administration was correlated to suppression of the PI3K/AKT signaling pathway. Inhibition of the proliferation of BC cells by PCB involved cell cycle (G2/M phase) arrest and apoptosis in vitro and in vivo. Low concentrations of PCB also significantly inhibited the migration and invasion abilities of BC cells. These findings suggest that PCB might be an effective agent for treatment of BC patients.

Objective: With the rapid development of cancer genomics and immunomics, some new treatments of small cell lung cancer (SCLC) are emerging. However, there are limitations to the clinical use of tumor tissue. Our study aimed to evaluate the potential use of bronchial washing fluid (BWF) in the liquid biopsy of SCLC. Methods: Twenty-one extensive SCLC (ES-SCLC) patients were enrolled in this study. For all patients, four sample types, BWF supernatant (BWFs), BWF precipitate (BWFp), plasma and tumor tissue, were collected before receiving chemotherapy, and one type, plasma, was collected after chemotherapy. All samples were conducted to NGS using the 1021-gene panel. The concordance rates of genomic profiling using NGS in the four types of samples were evaluated. Multiple clinical information was analyzed for correlation. Results: We successfully tested 20 BWFs samples, 21 BWFp samples, 21 tumor tissue samples, 20 pre-treatment plasma, and 13 post-treatment plasma of these 21 patients. The detectability of somatic mutations was 100% for BWFs, BWFp, tumor tissues, and post-treatment plasma, and only one pre-treatment plasma was absent with any mutation. Matched tumor tissue, BWFs, BWFp, and pre-treatment plasma samples were subsistent for 19 patients. For these patients, 204 genomic alterations were identified in tissue samples, while 189 (92.6%), 175 (85.5%), and 163 (79.9%) alterations were detected in the matched BWFs, BWFp, and pre-treatment plasma, respectively. Moreover, we found that the three tumor markers associated with SCLC have a lower sensitivity than genomic alterations. The endocrine resistance pathway was found enriched in hyponatremia patients which may be related to the hyponatremia. The TMBs of BWF, BWFp, and pre-treatment plasma samples all had a strong correlation with that of tissue samples. Both the VAF and the MVAF of mutations in post-treatment plasma were less than those in pre-treatment plasma, which was in accordance with the evaluation of curative effect. Conclusions: For ES-SCLC patients, the liquid biopsy of BWF showed a highly potential advantage to identify DNA alterations, which suggested that genomic analysis of BWF liquid biopsy may have clinical value as a supplement for tissue and blood detection. Through the restricted validation, it can be widely used in routine clinical practice.

Purpose: Nomogram prognostic models could greatly facilitate risk stratification and treatment strategies for cancer patients. We developed and validated a new nomogram prognostic model, named NCCBM, for breast cancer patients with brain metastasis (BCBM) using a large BCBM cohort from the SEER (Surveillance, Epidemiology, and End Results) database. Patients and Methods: Clinical data for 975 patients diagnosed from 2011 to 2014 were used to develop the nomogram prognostic model. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. The results were validated using an independent cohort of 542 BCBM patients diagnosed from 2014 to 2015. Results: The following variables were selected in the final prognostic model: age, race, surgery, radiation therapy, chemotherapy, laterality, grade, molecular subtype, and extracranial metastatic sites. The C-index for the model described here was 0.69 (95% CI, 0.67 to 0.71). The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The model was validated in an independent validation cohort with a C-index of 0.70 (95% CI, 0.68 to 0.73). Conclusion: We developed and validated a nomogram prognostic model for BCBM patients, and the proposed nomogram resulted in good performance.

The purpose of our study was to analyze the clinicopathologic features and surgical and oncological outcomes of adenoid cystic carcinoma (ACC) of the breast and to provide the basis for a clinical therapeutic schedule.

Chemotherapy is the standard adjuvant treatment for colon cancer. Chinese herbal formula PRM1201 improves the efficacy of chemotherapy when used in combination with Cetuximab or Bevacizumab in patients with metastatic colorectal cancer. This study aims to explore the benefits of treatment with chemotherapy plus PRM1201 in the postoperative adjuvant setting.

Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.

Whether muscle strength and physical performance should be components of sarcopenia remains controversial. This study evaluated the skeletal muscle index derived from computed tomography images at the 12th thoracic vertebra level (T12 SMI), handgrip strength, performance status, and their combination for predicting overall survival in patients with advanced non-small cell lung cancer.

MicroRNA (miRNA) is an important regulator for gene expression. Recent studies showed that some heterogenous miRNAs derived from both parasite and plant can regulate expression of mammalian gene in a cross-species or even a cross-kingdom manner. Here, we identified a Schistosoma japonicum miRNA (designated as sja-miR-61) that is present in the hepatocyte of mice infected with the parasite. The sja-miR-61 mimics significantly inhibited the migration of both mouse and human hepatoma cells in vitro. In a xenograft animal model, significant reductions of the tumor volume and weight were observed in mice inoculated with hepatoma cells transfected with sja-miR-61 mimics compared to the controls. We found that the in vivo inhibition of tumor growth was through its anti-angiogenesis activity. Mechanically, we identified the phosphoglycerate mutase 1 (PGAM1) gene as a target of sja-miR-61 and found that the sja-miR-61-mediated suppression of cell migration and anti-angiogenesis by cross-species down-regulation of PGAM1 expression. These data indicated that sja-miR-61 is a tumor suppressor miRNA that may have therapeutic potential for human cancers.

Immune checkpoint inhibitors (ICIs) have dramatically altered the treatment landscape for patients with melanoma. However, their use also generates unique immune-related adverse effects (irAEs). We performed a systematic review and network meta-analysis to compare the risk of pneumonitis associated with ICIs for patients with advanced or metastatic melanoma.